Synthesis of enamino ketones from 4,5-dihydropyrazoles

Article abstract of DOI:10.1134/S1070428007120111

Enamino ketones were synthesized in 97-99% yield by reactions of 4,5-dihydropyrazoles with 1,3-dicarbonyl compounds.

Full text of DOI:10.1134/S1070428007120111

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2007, Vol. 43, No. 12, pp. 1809–1812. © Pleiades Publishing, Ltd., 2007.
Original Russian Text © B.F. Kukharev, V.K. Stankevich, E.Kh. Sadykov, N.A. Lobanova, G.R. Klimenko, 2007, published in Zhurnal Organicheskoi Khimii,
2007, Vol. 43, No. 12, pp. 1807–1810.
Synthesis of Enamino Ketones from 4,5-Dihydropyrazoles
B. F. Kukharev, V. K. Stankevich, E. Kh. Sadykov, N. A. Lobanova, and G. R. Klimenko
Favorskii Irkutsk Institute of Chemistry, Siberian Division, Russian Academy of Sciences,
ul. Favorskogo 1, Irkutsk, 664033 Russia
e-mail: irk_inst_chem@irioch.irk.ru
Received January 29, 2007
Abstract—Enamino ketones were synthesized in 97–99% yield by reactions of 4,5-dihydropyrazoles with
1,3-dicarbonyl compounds.
DOI: 10.1134/S1070428007120111
Enamino ketones are versatile and readily acces-
sible synthons for the preparation of a wide series of
heterocyclic compounds; in addition, they exhibit bio-
logical activity [1–3]. Their chemical reactivity and
biological activity strongly depend on the nature of the
amine fragment. In the present work we were the first
to use 4,5-dihydropyrazoles as initial amine compo-
nent in the synthesis of enaminones. 4,5-Dihydropyr-
azoles themselves possess a high synthetic potential,
and their derivatives are known to exhibit versatile
biological activity [4]; therefore, enhancement of such
properties may be expected for enaminones derived
therefrom. Moreover, enaminones B derived from
dihydropyrazoles are characterized by more extended
conjugation system as compared to enaminones A that
have been studied most thoroughly [3]; higher degree
of electron density delocalization in the former should
increase the stability of structures B relative to struc-
tures like A.
··
·· ··
N
C
C
C
O
C
N
N
C
C
C
O
A
B
By heating equimolar amounts of 4,5-dihydropyra-
zole Ia–Id and dicarbonyl compound IIa, IIb, or III in
boiling benzene in the presence of a catalytic amount
of p-toluenesulfonic acid (no reaction occurred in the
absence of a catalyst) with simultaneous removal of
liberated water as azeotrope we obtained the corre-
sponding enamino ketones IVa–IVk in almost quan-
titative yield (Scheme 1).
Compounds IVa–IVk were isolated as crystalline
or viscous oily substances which underwent oxidation
on exposure to air and decomposition on attempted
Scheme 1.
R1
O
O
R2
R3
Me
R4
N
IIa, IIb
Me Me
O
N
R1
R4
O
Me
IVa–IVh
R2
R3
N
N
H
O
O
R1
1′ 2′
N
3′
III
6′
N
Ia–Id
4′
5′
Me
R2
R3
Me
IVi–IVk
I, R1 = R2 = R3 = H (a), Me (c); R3 = Me, R1 = R2 = H (b), Et (d); II, R4 = Me (a), OEt (b); IV, R4 = Me, R1 = R2 = R3 = H (a),
Me (c); R3 = Me, R1 = R2 = H (b), Et (d); R4 = OEt, R1 = R2 = R3 = H (e), Me (g), R3 = Me, R1 = R2 = H (f), Et (h); R3 = Me, R1 =
R2 = H (i), Et (k), R1 = R2 = R3 = Me (j).
1809

KUKHAREV et al.
1810
vacuum distillation (at a residual pressure of 1–2 mm);
however, they can be stored for a long time under
argon. Thus the products are less stable than enamino
ketones obtained from the same dicarbonyl compounds
and secondary cyclic amines, such as piperidine, mor-
pholine, etc.
545, 758, 800, 823, 851, 865, 917, 948, 972, 985,
1067, 1100, 1268, 1340, 1384, 1417, 1438, 1525, 1584,
1617, 2915, 2953, 3055. H NMR spectrum, δ, ppm:
1
2.11 s (3H, MeC=C), 2.65 s (3H, MeC=O), 2.96 t.d
3
3
(2H, 4-H, J4,5 = 10.2, J3,4 = 1.3 Hz), 3.64 t (2H, 5-H,
3J4,5 = 10.2 Hz), 5.07 s (1H, C=CH), 6.94 unresolved
13
triplet (1H, 3-H). C NMR spectrum, δC, ppm: 15.56
The IR spectra of enaminones IVa–IVk contained
absorption bands in the regions 1500–1583 and 1607–
1675 cm–1, which correspond to vibrations of the bond
system C=N–N–C=CH–C=O; bands in the region
3043–3083 cm–1 belong to stretching vibrations of the
(MeC=CH), 31.53 (MeC=O), 33.26 (C4), 44.10 (C5),
96.10 (C=CH), 145.38 (C3), 155.79 (MeC=C), 195.48
(C=O). Found, %: C 63.56; H 8.01; N 18.63.
C8H12N2O. Calculated, %: C 63.13; H 7.95; N 18.41.
1
=C–H bonds. In the H NMR spectra of IVa–IVd and
4-(5-Methyl-4,5-dihydro-1H-pyrazol-1-yl)pent-3-
en-2-one (IVb). Yield 98%, viscous oily substance. IR
spectrum, ν, cm–1: 497, 543, 773, 809, 867, 933, 960,
1052, 1065, 1100, 1167, 1265, 1313, 1340, 1352, 1409,
IVi–IVk we observed a singlet at δ 5.07–5.55 ppm,
which was assigned to the NC=CHC=O proton. The
corresponding signal in the spectra of enaminones
IVe–IVh obtained from ethyl acetoacetate was located
in a stronger field, at δ 4.58–4.92 ppm. The presence
of only one NC=CHC=O signal in the 1H NMR spectra
of compounds IVa–IVk suggests that they are formed
as a single isomer. Insofar as the =CH proton in IVa–
IVh shows no couplings with other protons (there are
no protons on the neighboring double-bonded carbon
atom and nitrogen atom), the isomer configuration
cannot be determined reliably. On the other hand, the
chemical shifts of the olefinic proton and the position
of signals from the double-bonded carbon atoms in the
13C NMR spectra of enaminones derived from acetyl-
acetone (ethyl acetoacetate) and cyclic secondary
amines [1], as well as the corresponding data for com-
pounds IVi–IVk, led us to presume that enamino
ketones IVa–IVh are cis-s-trans isomers.
1
1516, 1633, 2921, 2960, 3043. H NMR spectrum, δ,
3
ppm: 1.13 d (3H, 5-Me, J = 6.5 Hz), 2.00 s (3H,
2
3
MeC=C), 2.44 d.d.d (1H, 4-HA, J = 18.3, J4,5 = 3.2,
3J3,4 = 1.9 Hz), 2.52 s (3H, MeC=O), 3.05 d.d.d (1H,
2
3
3
4-HB, J = 18.3, J4,5 = 10.6, J3,4 = 1.5 Hz), 4.23 m
(1H, 5-H), 5.17 s (1H, C=CH), 6.82 unresolved triplet
(3-H). 13C NMR spectrum, δC, ppm: 15.87 (5-Me),
18.44 (MeC=C), 31.65 (MeC=O), 41.88 (C4), 52.29
(C5), 95.66 (C=CH), 144.86 (C3), 155.16 (MeC=C),
195.33 (C=O). Found, %: C 64.92; H 8.40; N 16.58.
C9H14N2O. Calculated, %: C 65.03; H 8.49; N 16.85.
4-(3,5,5-Trimethyl-4,5-dihydro-1H-pyrazol-1-yl)-
pent-3-en-2-one (IVc). Yield 97%, colorless crystals,
mp 78°C. IR spectrum, ν, cm–1: 537, 592, 675, 727,
767, 838, 933, 955, 1000, 1050, 1062, 1133, 1153,
1183, 1237, 1313, 1333, 1358, 1400, 1425, 1442, 1500,
1
1617, 2900, 2958. H NMR spectrum, δ, ppm: 1.57 s
EXPERIMENTAL
(6H, 5-Me), 2.01 s (3H, 3-Me), 2.10 s (3H, MeC=C),
2.63 s (3H, MeC=O), 2.80 s (2H, 4-H), 5.55 s (1H,
C=CH). 13C NMR spectrum, δC, ppm: 16.09 (MeC=C),
17.22 (3-Me), 26.30 (5-Me), 32.16 (MeC=O), 55.36
(C4), 64.60 (C5), 95.46 (C=CH), 152.80 (C3), 156.15
(MeC=C), 195.19 (C=O). Found, %: C 68.46; H 9.84;
N 14.81. C11H18N2O. Calculated, %: C 68.01; H 9.34;
N 14.42.
1
The H and 13C NMR spectra were recorded at
26°C on a Bruker DPX-400 spectrometer at 400 and
100 MHz, respectively, from solutions in CDCl3 using
HMDS as internal reference. The IR spectra were
measured on a Specord 75IR spectrophotometer from
samples prepared as thin films or KBr pellets.
Enaminones IVa–IVk (general procedure). A mix-
ture of 0.1 mol of dihydropyrazole Ia–Id, 0.1 mol of
dicarbonyl compound IIa, IIb, or III, and 0.01 g of
p-toluenesulfonic acid in 50 ml of benzene was heated
under reflux in a flask equipped with a Dean–Stark
trap until water no longer separated. The solvent was
distilled off, and the residue (an oily liquid) was dried
until constant weight by keeping at room temperature
at a residual pressure of 2 mm.
4-(3,5-Diethyl-5-methyl-4,5-dihydro-1H-pyrazol-
1-yl)pent-3-en-2-one (IVd). Yield 98%, viscous oily
substance. IR spectrum, ν, cm–1: 547, 600, 680, 792,
835, 979, 1059, 1097, 1181, 1307, 1349, 1373, 1420,
1
1455, 1528, 1630, 2886, 2964, 2980. H NMR spec-
3
trum, δ, ppm: 0.82 t (3H, 5-CH2CH3, J = 7.3 Hz),
3
1.14 t (3H, 3-CH2CH3, J = 7.5 Hz), 1.55 s (3H,
5-Me), 1.65 m (1H, 3-CHA), 2.08 s (3H, MeC=C),
3
2.16 m (1H, 3-CHB), 2.32 q (2H, 3-CH2, J = 7.5 Hz)
4-(4,5-Dihydro-1H-pyrazol-1-yl)pent-3-en-2-one
(IVa). Yield 98%, mp 68°C. IR spectrum, ν, cm–1: 480,
2.64 s (3H, MeC=O), 2.69 d (1H, 4-HA, 2J = 17.9 Hz),
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 12 2007

SYNTHESIS OF ENAMINO KETONES FROM 4,5-DIHYDROPYRAZOLES
1811
2
14.97 (CH3CH2), 16.21 (3-Me), 17.18 (MeC=C), 26.10
(5-Me), 55.50 (C4), 58.42 (OCH2), 64.45 (C5), 85.52
(C=CH), 150.02 (C3), 155.99 (MeC=C), 168.65 (C=O).
Found, %: C 64.34; H 9.06; N 12.37. C12H20N2O2. Cal-
culated, %: C 64.26; H 8.99; N 12.49.
2.89 d (1H, 4-HB, J = 17.9 Hz), 5.50 s (1H, C=CH).
13C NMR spectrum, δC, ppm: 8.10 (5-CH2CH3), 10.64
(3-CH2CH3), 17.11 (5-Me), 23.52 (5-CH2), 25.27
(MeC=C), 31.26 (3-CH2), 31.96 (MeC=O), 50.13 (C4),
67.92 (C5), 100.31 (C=CH), 156.94 (C3), 157.42
(MeC=C), 195.02 (C=O). Found, %: C 70.46; H 9.82;
N 12.17. C13H22N2O. Calculated, %: C 70.23; H 9.97;
N 12.60.
Ethyl 3-(3,5-diethyl-5-methyl-4,5-dihydro-1H-
pyrazol-1-yl)but-2-enoate (IVh). Yield 97%, viscous
oily substance. IR spectrum, ν, cm–1: 455, 533, 567,
632, 733, 800, 898, 932, 992, 1057, 1110, 1130, 1175,
1272, 1318, 1343, 1392, 1428, 1468, 1583, 1642, 1667,
Ethyl 3-(4,5-dihydro-1H-pyrazol-1-yl)but-2-en-
oate (IVe). Yield 97%, viscous oily substance. IR spec-
trum, ν, cm–1: 483, 525, 648, 709, 833, 903, 925, 998,
1047, 1118, 1158, 1272, 1342, 1358, 1420, 1567, 1593,
1675, 2905, 2938, 2983, 3083. H NMR spectrum, δ,
ppm: 1.25 t (3H, CH2CH3, J = 7.2 Hz), 2.61 s (3H,
MeC=C), 2.93 t.d (2H, 4-H, J4, 5 = 10.1, J3, 4
1.1 Hz), 3.58 t (2H, 5-H, J4,5 = 10.1 Hz), 4.10 q (2H,
OCH2, J = 7.2 Hz), 4.58 s (1H, C=CH), 6.85 unre-
1
2892, 2950, 2987. H NMR spectrum, δ, ppm: 0.76 m
(3H, 5-CH2CH3), 1.07 m (3H, 3-CH2CH3), 1.18 m
(3H, OCH2CH3), 1.47 s (3H, 5-Me), 1.58 m (1H,
5-CHA), 2.11 m (1H, 5-CHB), 2.24 m (2H, 3-CH2),
1
3
2
3
3
2.54 s (3H, MeC=C), 2.60 d (1H, 4-HA, J = 17.7 Hz),
=
2
2
3
2.81 d (1H, 4-HB, J = 17.7 Hz), 4.02 q.d (OCH2, J =
3
13
3
1.7, J = 7.1 Hz), 4.92 s (C=CH). C NMR spectrum,
δC, ppm: 8.20 (5-CH2CH3), 10.72 (3-CH2CH3), 14.61
(OCH2CH3), 16.81 (5-Me), 23.46 (5-CH2), 25.27
(MeC=C), 30.98 (3-CH2), 50.03 (C4), 58.28 (OCH2),
67.68 (C5), 84.13 (C=CH), 155.40 (C3), 156.65
(MeC=C), 169.09 (C=O). Found, %: C 66.25; H 9.29;
N 11.02. C14H24N2O2. Calculated, %: C 66.63; H 9.59;
N 11.10.
13
solved triplet (1H, 3-H). C NMR spectrum, δC, ppm:
14.50 (CH2CH3), 15.36 (MeC=C), 33.47 (C4), 44.47
(C5), 58.51 (OCH2), 86.28 (C=CH), 144.26 (C3),
156.53 (MeC=C), 168.58 (C=O). Found, %: C 59.20;
H 7.54; N 15.96. C9H14N2O2. Calculated, %: C 59.32;
H 7.74; N 15.37.
Ethyl 3-(5-methyl-4,5-dihydro-1H-pyrazol-1-yl)-
but-2-enoate (IVf). Yield 98%, viscous oily substance.
IR spectrum, ν, cm–1: 483, 532, 642, 715, 775, 802,
842, 883, 933, 950, 1023, 1041, 1092, 1122, 1250,
1292, 1308, 1322, 1342, 1350, 1400, 1550, 1580, 1667,
5,5-Dimethyl-3-(5-methyl-4,5-dihydro-1H-pyra-
zol-1-yl)cyclohex-2-en-1-one (IVi). Yield 97%, vis-
cous oily substance. IR spectrum, ν, cm–1: 433, 457,
497, 665, 697, 717, 797, 817, 853, 883, 900, 933, 947,
987, 1007, 1060, 1073, 1097, 1140, 1163, 1180, 1233,
1260, 1353, 1413, 1540, 1626, 2833, 2940, 3053.
1H NMR spectrum, δ, ppm: 1.13 s (3H, 5′-Me), 1.18 s
1
2833, 2858, 2883, 2915, 2957, 3058. H NMR spec-
3
trum, δ, ppm: 1.22 d (3H, 5-Me, J = 6.18 Hz), 1.25 t
(3H, CH2CH3, 3J = 7.1 Hz), 2.51 d.d.d (1H, 4-HA, 2J =
3
(3H, 5′-Me), 1.29 d (3H, 5-Me, J = 6.1 Hz), 2.21 m
3
3
2
3
18.0, J4,5 = 3.5, J3,5 = 1.9 Hz), 2.60 s (3H, MeC=C),
(2H, 4′-H), 2.59 d.d.d (1H, 4-HA, J = 18.1, J = 3.5,
2
3
3
2
3.13 d.d.d (1H, 4-HB, J = 18.0, J4,5 = 10.7, J3,5
=
1.7 Hz), 2.67 s (2H, 6′-H), 3.22 d.d.d (1H, 4-HB, J =
1.6 Hz), 4.10 q.d (OCHA, 2J = 2.1, 3J = 7.1 Hz), 4.23 m
18.1, J = 10.1, 3J = 1.4 Hz), 4.28 m (1H, 5-H), 5.17 s
3
3
13
(1H, 5-H), 4.76 s (1H, C=CH), 6.68 t (3-H, J =
(1H, C=CH), 6.91 unresolved triplet (3-H). C NMR
1.6 Hz). 13C NMR spectrum, δC, ppm: 14.55 (CH3CH2),
15.64 (5-Me), 18.54 (MeC=C), 42.04 (C4), 52.02 (C5),
58.51 (OCH2), 85.81 (C=CH), 143.17 (C3), 155.64
(MeC=C), 168.77 (C=O). Found, %: C 61.38; H 8.57;
N 14.38. C10H16N2O2. Calculated, %: C 61.20; H 8.22;
N 14.27.
spectrum, δC, ppm: 18.21 (5-Me), 28.01 (5′-Me), 28.26
(5′-Me), 32.00 (C5′), 39.71 (C4), 41.58 (C4′), 49.64
(C6′), 51.65 (C5), 96.79 (C2′), 144.45 (C3), 157.15 (C3′),
196.06 (C=O). Found, %: C 69.64; H 8.45; N 13.26.
C12H18N2O. Calculated, %: C 69.87; H 8.79; N 13.58.
5,5-Dimethyl-3-(3,5,5-trimethyl-4,5-dihydro-1H-
pyrazol-1-yl)cyclohex-2-en-1-one (IVj). Yield 97%,
viscous oily substance. IR spectrum, ν, cm–1: 413, 460,
500, 533, 593, 687, 741, 793, 820, 833, 860, 880, 900,
925, 953, 990, 1013, 1033, 1107, 1137, 1144, 1240,
Ethyl 3-(3,5,5-trimethyl-4,5-dihydro-1H-pyrazol-
1-yl)but-2-enoate (IVg). Yield 99%, mp 96°C. IR
spectrum, ν, cm–1: 628, 725, 798, 842, 888, 907, 958,
983, 1000, 1040, 1095, 1125, 1100, 1247, 1317, 1358,
1377, 1422, 1558, 1640, 1670, 2915, 2933, 2980.
1
1271, 1367, 1420, 1543, 1613, 2867, 2953. H NMR
3
1H NMR spectrum, δ, ppm: 1.25 t (3H, CH3CH2, J =
spectrum, δ, ppm: 1.08 s (6H, 5′-Me), 1.55 s (6H,
5-Me), 2.00 s (3H, 3-Me), 2.13 s (2H, 4′-H), 2.61 s
(2H, 4-H), 2.81 s (2H, 6′-H), 5.37 s (1H, 2′-H).
13C NMR spectrum, δC, ppm: 16.74 (3-Me), 26.61
7.1 Hz), 1.56 s (6H, 5-Me), 1.98 s (3H, 3-Me), 2.54 s
3
(3H, MeC=C), 2.75 s (2H, 4-H), 4.06 q (OCH2, J =
13
7.1 Hz), 4.92 s (C=CH). C NMR spectrum, δC, ppm:
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 12 2007

KUKHAREV et al.
1812
(5-Me), 29.43 (5′-Me), 33.16 (C5′), 42.34 (C4′), 50.30
(C6′), 55.87 (C4), 65.50 (C5), 97.02 (C3′), 154.31 (C3),
158.91 (C2′), 197.34 (C=O). Found, %: C 71.31;
H 9.14; N 11.53. C14H22N2O. Calculated, %: C 71.76;
H 9.46; N 11.95.
(5-CH2), 28.19 (5′-Me), 28.71 (5′-Me), 30.55 (3-CH2),
32.26 (C5′), 41.35 (C4′), 49.37 (C4), 49.85 (C6′), 68.10
(C5), 103.21 (C2′), 158.56 (C3), 159.03 (C3′), 196.92
(C=O). Found, %: C 73.16; H 9.87; N 10.43.
C16H26N2O. Calculated, %: C 73.24; H 9.99; N 10.68.
3-(3,5-Diethyl-5-methyl-4,5-dihydro-1H-pyrazol-
1-yl)-5,5-dimethylcyclohex-2-en-1-one (IVk). Yield
98%, viscous oily substance. IR spectrum, ν, cm–1:
420, 472, 500, 547, 592, 673, 687, 727, 740, 799, 820,
860, 879, 925, 987, 1020, 1053, 1107, 1237, 1240,
1251, 1287, 1357, 1413, 1453, 1547, 1607, 2872, 2960.
1H NMR spectrum, δ, ppm: 0.78 t (3H, 5-CH2CH3,
3J = 7.1 Hz), 1.07 s (6H, 5′-Me), 1.15 t (3H,
REFERENCES
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3
3-CH2CH3, J = 7.6 Hz), 1.54 s (3H, 5-Me), 1.63 m
(1H, 5-CHA), 2.16 s (2H, 4′-H), 2.21 m (1H, 5-CHB),
2.33 m (2H, 3-CH2), 2.67 m (2H, 6′-H), 2.70 d (1H,
2
2
4-HA, J = 17.9 Hz), 2.90 d (1H, 4-HB, J = 17.9 Hz),
13
5.39 s (1H, C=CH). C NMR spectrum, δC, ppm: 8.0
4. Kost, A.N. and Ershov, V.V., Usp. Khim., 1958, vol. 27,
(5-CH2CH3), 10.63 (3-CH2CH3), 23.43 (5-Me), 25.11
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 12 2007